Papillomaviruses have a remarkable infectious cycle that depends on the development of a stratified epithelium. In this life cycle, there are three different modes of viral DNA replication. The virus initially infects the lower, dividing layers of the epithelium; viral DNA is transported to the nucleus where it must escape intrinsic host defenses and establish the genome as a stable, extra-chromosomal, autonomously replicating element. Next, in the maintenance phase, genomes replicate at low copy number in concert with host DNA and are partitioned to daughter cells upon cell division. Finally, as infected cells differentiate and traffic to the surface of the epithelium, high level viral DNA amplification is triggered to generate new progeny virus. We have studied all three phases of viral replication in this review cycle. Our objective is to define the precise molecular mechanisms involved in viral and cellular replication. This insight will enhance our ability to design therapeutics for viral infection and associated cancers.